腺苷A2A受体在实验性自身免疫性重症肌无力中的机制研究
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摘要
目的：1、揭示A2AR在实验性自身免疫性重症肌无力（ExperimentalAutoimmune Myasthenia Gravis，EAMG）发生、发展中的作用；2、证实A2AR是通过作用于EAMG病理性T细胞进而影响EAMG的发病过程；3、探讨激活A2AR调节EAMG疾病进程的具体分子机制。
方法：1、通过主动免疫建立大鼠EAMG动物模型；2、组织病理学实验技术检测A2AR的表达和相关病理学改变；3、FACS方法检测A2AR在CD4+T细胞、CD8+T细胞和B细胞上的分布；4、体外加入A2AR激动剂CGS21680、A2AR拮抗剂SCH58261、ZM241385，cAMP拮抗剂H-89后ELISA方法检测细胞培养上清中anti-AChR IgG的分泌情况、3H标记技术检测淋巴细胞增殖能力、FACS方法检测Th1、Th2、Th17及Treg四种亚型的改变；5、免疫磁珠法分选细胞获得B细胞加入CGS21680后ELISA方法检测细胞培养上清中anti-AChR IgG的分泌情况、3H标记技术检测B淋巴细胞增殖能力；6、于一次免疫前一天和二次免疫前一天分别给予CGS21680，观察老鼠体重和ELISA方法检测血清中anti-AChR IgG的分泌情况、FACS方法检测Th1、Th2、Th17及Treg四种亚型的改变。
结果：1、免疫组化结果显示，与CFA组相比较，EAMG组大鼠脾和淋巴结中A2AR的表达下降，差异显著（P脾<0.001，P淋巴结<0.05）；2、流式结果显示，与CFA组比较，EAMG大鼠CD4+T细胞、CD8+T细胞和B细胞上A2AR的表达均下降，差异显著（P脾CD4+T细胞<0.001，P脾CD8+T细胞<0.05，P脾B细胞<0.01，P淋巴结CD4+T细胞<0.001，P淋巴结CD8+T细胞<0.01，P淋巴结B细胞<0.05）；3、ELISA结果显示，用A2AR激动剂CGS21680体外激活AChR特异性淋巴细胞上面的A2AR受体，能够抑制AChR特异性淋巴细胞anti-AChR IgG的分泌，具有统计学意义（PCGS21680<0.001），并且这种抑制作用能够被A2AR拮抗剂SCH58261、ZM241385和PKA拮抗剂H-89所阻断，具有统计学意义（PSCH58261<0.05，PZM241385<0.05， PH-89<0.05）；4、3H胸腺嘧啶插入实验结果显示，体外激活AChR特异性淋巴细胞上面的A2AR受体，能够抑制AChR特异性淋巴细胞增殖能力，具有统计学意义（P <0.05）；5、体外激活AChR特异性B淋巴细胞上面的A2AR受体，对B淋巴细胞anti-AChR IgG分泌能力和增殖能力影响较小；6、一次免疫前一天预防性治疗给予CGS21680发现，和EAMG模型鼠比较，预防性给药组老鼠体重降低变轻（P<0.001）、症状缓解（P<0.001）、血清中anti-AChR IgG分泌减少（P<0.001），AChR特异性淋巴细胞增殖能力变弱（P<0.001），Th四种细胞亚群失衡得以缓解；7、二次免疫前一天治疗性给予CGS21680发现，和EAMG模型鼠比较，治疗性给药组老鼠体重降低变轻（P <0.05）、症状缓解（P<0.05）、血清中anti-AChR IgG分泌减少（P <0.05），AChR特异性淋巴细胞增殖能力变弱（P<0.05）。
结论：1、EAMG发生发展过程中伴随着保护性受体A2AR的表达数量的下降；2、A2AR特异性激动剂CGS21680激活A2AR后对EAMG的疾病进程具有缓解作用；3、A2AR特异性激动剂CGS21680激活A2AR能够抑制AChR特异性T细胞的功能；4、A2AR特异性激动剂CGS21680激活A2AR对AChR特异性B细胞的功能影响较小；5、激活A2AR后能够逆转EAMG中Th1/Th2/Th17/Treg四种辅助性T细胞亚群的功能失衡状态。
Objective: To investigate the relationship between Adenosine A2A receptor (A2AR)and Experimental Autoimmune Myasthenia Gravis (EAMG); to investigate whetherA2AR activation holds the potential for impacting the severity of EAMG; toinvestigate whether A2AR could impact EAMG severity through impact the banlancebetween four AChR-specific Th subsets.
Methods: EAMG were induced following immunization of Lewis rats with theacetylcholine receptor (AChR) R97–116peptide. We used immunohistochemistry totest the A2AR expression in spleen and lymph node. The expression of A2AR onCD4+T cells, CD8+T cells and B cells were detected by FACs analysis. ELISAmethod was used to detect the secretion of anti-AChR antibody in supernatant afterincubation with A2AR agonist CGS21680, A2AR antagonist SCH58261, ZM241385and cAMP antagonist H-89, then the proliferative ability of T lymphocytes wasdetected by3H incorporation. Th subsets distribution was meseasured by FACsanalysis.
Results: Compared with CFA control group, the EAMG rats showed lower lever ofA2AR expression in both spleen and lymph node in immunohistochemistryexperiment (Pspleen<0.001, Plymph node<0.05); FACs analysis results turned out thatthe expression of A2AR of EAMG rats were significantly decreased in all CD4+Tcells, CD8+T cells and B cells comprared with CFA group (Pspleen CD4+T cells<0.001, Pspleen CD8+T cells<0.05, PspleenB cells<0.01, Plymph nodeCD4+T cells<0.001, Plymph nodeCD8+T cells<0.01, Plymph nodeB cells<0.05); the secretion of anti-AChR antibody was significantlydecreased after incubation with A2AR agonist CGS21680and this inhibition can beblocked by A2AR antagonist SCH58261, ZM241385and cAMP antagonist H-89 (PCGS21680<0.001, PSCH58261<0.05, PZM241385<0.05, PH-89<0.05). Besides, A2ARactivation could inhibit the proliferation ability of AChR-specific T cells (P <0.05).However A2AR activation had little effect on B cells. We also determined that thedevelopment of EAMG was accompanied by a T helper cell imbalance that could berestored following A2AR stimulation that resulted in increased Treg levels and areduction in Th1, Th2and Th17cell subtypes. An EAMG preventive treatmentregimen was established that consisted of CGS21680(A2AR agonist) administration1day prior to EAMG induction. Administration of CGS2168029days post EAMGinduction (therapeutic treatment) also ameliorated disease severity.
Conclusion: A2AR expression is decreased in EAMG progression; A2AR activationhold the potential for impacting the severity of EAMG; A2AR activation hold thepotential for inhibiting AChR-sepecific T cells proliferation and function; A2ARactivation had little effect on B cells and A2AR activation can reversed theimbanlance between Th1/Th2/Th17/Treg subsets. We concluded that A2AR agonistsmay represent a new class of compounds that can be developed for use in thetreatment of MG or other T cell-and B cell-mediated autoimmune diseases.
方法：1、通过主动免疫建立大鼠EAMG动物模型；2、组织病理学实验技术检测A2AR的表达和相关病理学改变；3、FACS方法检测A2AR在CD4+T细胞、CD8+T细胞和B细胞上的分布；4、体外加入A2AR激动剂CGS21680、A2AR拮抗剂SCH58261、ZM241385，cAMP拮抗剂H-89后ELISA方法检测细胞培养上清中anti-AChR IgG的分泌情况、3H标记技术检测淋巴细胞增殖能力、FACS方法检测Th1、Th2、Th17及Treg四种亚型的改变；5、免疫磁珠法分选细胞获得B细胞加入CGS21680后ELISA方法检测细胞培养上清中anti-AChR IgG的分泌情况、3H标记技术检测B淋巴细胞增殖能力；6、于一次免疫前一天和二次免疫前一天分别给予CGS21680，观察老鼠体重和ELISA方法检测血清中anti-AChR IgG的分泌情况、FACS方法检测Th1、Th2、Th17及Treg四种亚型的改变。
结果：1、免疫组化结果显示，与CFA组相比较，EAMG组大鼠脾和淋巴结中A2AR的表达下降，差异显著（P脾<0.001，P淋巴结<0.05）；2、流式结果显示，与CFA组比较，EAMG大鼠CD4+T细胞、CD8+T细胞和B细胞上A2AR的表达均下降，差异显著（P脾CD4+T细胞<0.001，P脾CD8+T细胞<0.05，P脾B细胞<0.01，P淋巴结CD4+T细胞<0.001，P淋巴结CD8+T细胞<0.01，P淋巴结B细胞<0.05）；3、ELISA结果显示，用A2AR激动剂CGS21680体外激活AChR特异性淋巴细胞上面的A2AR受体，能够抑制AChR特异性淋巴细胞anti-AChR IgG的分泌，具有统计学意义（PCGS21680<0.001），并且这种抑制作用能够被A2AR拮抗剂SCH58261、ZM241385和PKA拮抗剂H-89所阻断，具有统计学意义（PSCH58261<0.05，PZM241385<0.05， PH-89<0.05）；4、3H胸腺嘧啶插入实验结果显示，体外激活AChR特异性淋巴细胞上面的A2AR受体，能够抑制AChR特异性淋巴细胞增殖能力，具有统计学意义（P <0.05）；5、体外激活AChR特异性B淋巴细胞上面的A2AR受体，对B淋巴细胞anti-AChR IgG分泌能力和增殖能力影响较小；6、一次免疫前一天预防性治疗给予CGS21680发现，和EAMG模型鼠比较，预防性给药组老鼠体重降低变轻（P<0.001）、症状缓解（P<0.001）、血清中anti-AChR IgG分泌减少（P<0.001），AChR特异性淋巴细胞增殖能力变弱（P<0.001），Th四种细胞亚群失衡得以缓解；7、二次免疫前一天治疗性给予CGS21680发现，和EAMG模型鼠比较，治疗性给药组老鼠体重降低变轻（P <0.05）、症状缓解（P<0.05）、血清中anti-AChR IgG分泌减少（P <0.05），AChR特异性淋巴细胞增殖能力变弱（P<0.05）。
结论：1、EAMG发生发展过程中伴随着保护性受体A2AR的表达数量的下降；2、A2AR特异性激动剂CGS21680激活A2AR后对EAMG的疾病进程具有缓解作用；3、A2AR特异性激动剂CGS21680激活A2AR能够抑制AChR特异性T细胞的功能；4、A2AR特异性激动剂CGS21680激活A2AR对AChR特异性B细胞的功能影响较小；5、激活A2AR后能够逆转EAMG中Th1/Th2/Th17/Treg四种辅助性T细胞亚群的功能失衡状态。
Objective: To investigate the relationship between Adenosine A2A receptor (A2AR)and Experimental Autoimmune Myasthenia Gravis (EAMG); to investigate whetherA2AR activation holds the potential for impacting the severity of EAMG; toinvestigate whether A2AR could impact EAMG severity through impact the banlancebetween four AChR-specific Th subsets.
Methods: EAMG were induced following immunization of Lewis rats with theacetylcholine receptor (AChR) R97–116peptide. We used immunohistochemistry totest the A2AR expression in spleen and lymph node. The expression of A2AR onCD4+T cells, CD8+T cells and B cells were detected by FACs analysis. ELISAmethod was used to detect the secretion of anti-AChR antibody in supernatant afterincubation with A2AR agonist CGS21680, A2AR antagonist SCH58261, ZM241385and cAMP antagonist H-89, then the proliferative ability of T lymphocytes wasdetected by3H incorporation. Th subsets distribution was meseasured by FACsanalysis.
Results: Compared with CFA control group, the EAMG rats showed lower lever ofA2AR expression in both spleen and lymph node in immunohistochemistryexperiment (Pspleen<0.001, Plymph node<0.05); FACs analysis results turned out thatthe expression of A2AR of EAMG rats were significantly decreased in all CD4+Tcells, CD8+T cells and B cells comprared with CFA group (Pspleen CD4+T cells<0.001, Pspleen CD8+T cells<0.05, PspleenB cells<0.01, Plymph nodeCD4+T cells<0.001, Plymph nodeCD8+T cells<0.01, Plymph nodeB cells<0.05); the secretion of anti-AChR antibody was significantlydecreased after incubation with A2AR agonist CGS21680and this inhibition can beblocked by A2AR antagonist SCH58261, ZM241385and cAMP antagonist H-89 (PCGS21680<0.001, PSCH58261<0.05, PZM241385<0.05, PH-89<0.05). Besides, A2ARactivation could inhibit the proliferation ability of AChR-specific T cells (P <0.05).However A2AR activation had little effect on B cells. We also determined that thedevelopment of EAMG was accompanied by a T helper cell imbalance that could berestored following A2AR stimulation that resulted in increased Treg levels and areduction in Th1, Th2and Th17cell subtypes. An EAMG preventive treatmentregimen was established that consisted of CGS21680(A2AR agonist) administration1day prior to EAMG induction. Administration of CGS2168029days post EAMGinduction (therapeutic treatment) also ameliorated disease severity.
Conclusion: A2AR expression is decreased in EAMG progression; A2AR activationhold the potential for impacting the severity of EAMG; A2AR activation hold thepotential for inhibiting AChR-sepecific T cells proliferation and function; A2ARactivation had little effect on B cells and A2AR activation can reversed theimbanlance between Th1/Th2/Th17/Treg subsets. We concluded that A2AR agonistsmay represent a new class of compounds that can be developed for use in thetreatment of MG or other T cell-and B cell-mediated autoimmune diseases.
引文
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